The present invention relates to an assay for detecting emetic activity in test compounds that are useful as type 4 phospodiesterase (PDE 4) inhibitors. Such compounds have important biological activity and can be used in treating or preventing asthma and other inflammatory diseases and conditions. (Harbinson et al., 1997; Karlsson & Aldous, 1997; Silvestre et al., 1998; Nieman et al., 1998; Nicholson & Shadid, 1994). However, these agents are known to cause emesis in man and in various animal species (Silvestre et al., 1998; Murdoch et al., 1998; Robichaud et al., 1998; Heaslip & Evans, 1995; Humpel et al., 1986; Horowski & Sastre-y-Hernandez, 1985). This debilitating side effect is a great impairment to the therapeutic potential of this new class of drugs.
Consequently, one object of the present invention was to elucidate the mechanism by which PDE 4 inhibitors trigger emesis.
Another object was to provide an assay for emesis that is reliable.
More particularly, an object of the present invention was to investigate the involvement of the noradrenergic nervous system in PDE 4 inhibitor-induced emesis and to provide an assay for emetic activity in these compounds.
Further, this assay is particularly useful for the identification of the locus of action of test compounds.
According to an aspect of the invention, the present assay is useful in identifying a test compound having activity in a cerebral and/or a peripheral locus of action. Therefore it is a useful application to select a test compound that is capable of crossing the blood-brain barrier.
These and other objects will become apparent to those of ordinary skill from the teachings provided herein.